SUMMARY OF WORK: PURPOSE: Seven years ago, I proposed a new model of the immune system (the Danger model) based on the assumption that the immune system's function is to discriminate between dangerous and harmless things rather than self and non-self. Because this model has tremendous implications for such subjects as cancer, transplantation, neonatal vaccines, parasitology, and autoimmunity, we have been testing its basic premises and its applicability in several areas. RESULTS FROM THE PAST YEAR: 1) TESTING THE BASIC PREMISE OF THE DANGER MODEL (Danger signals from injured tissues initiate immune responses.) We found that A) Danger signals from exogenous sources, such as bacteria, induce apoptotic death of dendritic cells, whereas natural endogenous alarm signals do not. B) pretreatment with IFNalpha protects DCs from death by bacterial products. C) mice missing the IFNalpha receptor do not respond well to LPS. 2) TRANSPLANTATION: A) T cells maturing in an animal carrying a long healed heart graft do not reject the graft, showing that the presence of "foreign" antigen does not elicit a rejection response in the absence of alarm signals. B) by gene chip analysis, there are about 100 mRNAs that differ between recent and longstanding heart grafts. Some of these encompass such wound-healing molecules as the thrombospondin receptor, metalloproteases etc. Thus recent grafts may send signals that initiate rejection. 3) TOLERANCE: A) oral administration of Factor IX induces immunological tolerance and corrects the bleeding time in hemophiliac mice. 4) CLASS CONTROL oral administration of antigen induces memory T cells that use dendritic cells to communicate with naive T cells and change the class of the ensuing response.